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A Mutation in the Surfactant Protein B Gene Responsible for Fatal Neonatal Respiratory Disease in Multiple Kindreds

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A Mutation in the Surfactant Protein B Gene Responsible for Fatal Neonatal Respiratory Disease in Multiple Kindreds A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. L M Nogee, … , D E deMello, H R Colten J Clin Invest. 1994;93(4):1860-1863. https://doi.org/10.1172/JCI117173. Research Article To determine the molecular defect accounting for the deficiency of pulmonary surfactant protein B (SP-B) in full-term neonates who died from respiratory failure associated with alveolar proteinosis, the sequence of the SP-B transcript in affected infants was ascertained. A frameshift mutation consisting of a substitution of GAA for C in codon 121 of the SP-B cDNA was identified. The three affected infants in the index family were homozygous for this mutation, which segregated in a fashion consistent with autosomal recessive inheritance of disease. The same mutation was found in two other unrelated infants who died from alveolar proteinosis, one of whom was also homozygous, and in the parents of an additional unrelated, affected infant, but was not observed in 50 control subjects. We conclude that this mutation is responsible for SP-B deficiency and neonatal alveolar proteinosis in multiple families and speculate that the disorder is more common than was recognized previously. Find the latest version: https://jci.me/117173/pdf Rapid Publication A Mutation in the Surfactant Protein B Gene Responsible for Fatal Neonatal Respiratory Disease in Multiple Kindreds Lawrence M. Nogee, * Gerard Gamier,t Harry C. Dietz, * Lori Singer,t Anne M. Murphy, * Daphne E. deMello,I and Harvey R. Coltent *Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; $Department of Pediatrics, Washington University School ofMedicine, St. Louis, Missouri 63110; and §Department ofPathology, St. Louis University School ofMedicine, St. Louis, Missouri 63117 Abstract (CAP) is a recognized familial cause of fatal respiratory disease in full-term infants (3-6). These observations suggest that an To determine the molecular defect accounting for the deficiency inherited deficiency of SP-B may cause this disorder and that of pulmonary surfactant protein B (SP-B) in full-term neonates abnormalities of surfactant proteins due to genetic mecha- who died from respiratory failure associated with alveolar pro- nisms could cause respiratory disease. To test these hypotheses teinosis, the sequence of the SP-B transcript in affected infants and to elucidate the molecular mechanisms responsible for the was ascertained. A frameshift mutation consisting of a substitu- lack of SP-B in these infants, we analyzed the SP-B transcripts tion of GAA for C in codon 121 of the SP-B cDNA was identi- in infants with CAP from unrelated families and compared fied. The three affected infants in the index family were homo- them with previously published SP-B cDNA and genomic se- zygous for this mutation, which segregated in a fashion consis- quences (7-10). tent with autosomal recessive inheritance of disease. The same mutation was found in two other unrelated infants who died Methods from alveolar proteinosis, one of whom was also homozygous, and in the parents of an additional unrelated, affected infant, Patients. The clinical course of infants from the index family (patients in We conclude that 11. 1, II.5, and II.6) and patient CAP-2 has been described previously (2, but was not observed 50 control subjects. 6). Patient CAP-3 was a 3-kg Caucasian female who developed respira- this mutation is responsible for SP-B deficiency and neonatal tory distress shortly after birth and who subsequently required intuba- alveolar proteinosis in multiple families and speculate that the tion, mechanical ventilation, and extracorporeal membrane oxygena- disorder is more common than was recognized previously. (J. tion. Open lung biopsy at 2 mo of age demonstrated characteristic Clin. Invest. 1994.93:1860-1863.) Key words: newborn * respi- findings of alveolar proteinosis: distal airspaces were filled with granu- ratory distress syndrome * pulmonary alveolar proteinosis lar, eosinophilic material that stained positively with periodic acid- bronchopulmonary dysplasia * lung diseases Schiff reagent, with foamy macrophages suspended in the protein- aceous material. She died at age 3 mo from respiratory failure; findings of alveolar proteinosis were also present at autopsy. Lung tissue from Introduction patients CAP-2 and CAP-3 was analyzed for SP-B content by immuno- histochemical staining and protein blotting as described previously A developmentally determined lack of pulmonary surfactant, (2). Control blood samples were obtained from healthy adult volun- the mixture of lipids and specific proteins that reduces alveolar teers without symptoms of pulmonary disease. surface tension, is recognized as the principal cause ofthe respi- cDNA preparation and sequencing. Total cellular RNA was pre- ratory distress syndrome in infants born prematurely (1). A pared from lung tissue frozen at the time of biopsy (patient 11.5) or deficiency of surfactant protein B (SP-B), ' an 8,000-D lung- rapid autopsy (patient II.6) by an acid phenol extraction method ( 11 ). specific protein, was recently demonstrated in three full-term Overlapping cDNA clones (spanning nucleotides 15-650, 22-761, siblings who died from respiratory failure associated with histo- 682-1405, and 1 172-1947) were generated by reverse transcription pathologic changes of alveolar proteinosis (2). SP-B has an (RT) of 5 jig of total cellular RNA using SP-B-specific antisense important role in the surface tension-lowering properties of primers, followed by PCR amplification, and subcloning the products surfactant, and congenital alveolar proteinosis into a plasmid vector (TAR cloning vector; Invitrogen, San Diego, CA) pulmonary according to the methods suggested by the manufacturer. For the most 5' and 3' sequences, genomic DNA sequences from nucleotides - 108 Address correspondence to Dr. Lawrence M. Nogee, Division of Neon- to 395 and 9052 to 9399 were amplified by PCR from patient II.6 and atology, CMSC 210, The Johns Hopkins Children's Center, 600 North subcloned. For the cDNA clone whose partial sequence is shown in Fig. Wolfe Street, Baltimore, MD 21287-3200. 1, the antisense SP-B-specific primer used was 5'-AGA GCC CTG Received for publication 18 October 1993 and in revised form 6 CAG AGC CAG CAA TAG GGG AGA-3', and the sense primer used December 1993. was 5'-ATG GCT GAG TCA CAC CTG CTG CAG TGG CTG-3'. 5 ,gg of plasmid DNA containing the cDNA insert was denatured and 1. Abbreviations used in this paper: CAP, congenital alveolar proteino- sequenced by the dideoxy chain termination method ( 12) (Sequenase, sis; RT, reverse transcription; SP, surfactant protein. V2.0; United States Biochemical Corp., Cleveland, OH) with incorpo- ration of 3S-dATP. The sequencing primer used was 5'-TTC CTG J. Clin. Invest. GAG CAG GAG TGC-3'. The products were separated on a 6% dena- © The American Society for Clinical Investigation, Inc. turing polyacrylamide gel and visualized by autoradiography. Se- 002 1-9738/94/04/1860/04 $2.00 quence analysis was repeated on two separately generated PCR prod- Volume 93, April 1994, 1860-1863 ucts from each of two affected siblings (patients II.5 and 11.6). 1860 Nogee, Garnier, Dietz, Singer, Murphy, deMello, and Colten A C G T T Figure 1. DNA se- A NORMAL SP-B cDNA G quence demonstrating _ l2lins2 mutation. The 1 2 3 4 5 6' 7 + 11 C DNA sequence 910 C ladder 2Q0 Kb c of the sense strand of a A * cDNA B SP-B DEFICIENT cDNAs A clone from the G * index infant with SP-B C-GAA C A ; deficiency (patient 11.5) 1 2 4 5 6 *8 11 T 1 AC910 AAAA C in the region of the mu- A tation is shown. The 375 967 1316 1972 T I.3'8 normal SP-B cDNA se- C- GAA GC C 119 120 121 122 123 quenceislistedbelow -- ACA for comparison. In co- 1 2 |3 4 5 6 7 8 910 11 A Tyr Phe Pro Leu Val * * - AAA NORMALTOTTC ~CCTG GTC . NORMAL TAC TTC PCC CTG GTC donsubstitution121 thereof isGAAa 3-bpfor 375 696.7 967 316 1972 4316 SP-B DEFICIENT: TAC TTC M CCC TGG C, marked with aster- Tyr Phe Asp Pro Trp isks. Figure 2. Aberrant splicing of SP-B-deficient transcripts. The normal SP-B mRNA structure is depicted in A, with the relative size of each exon indicated. The narrow bars indicate the untranslated regions. The two SP-B-deficient transcripts are depicted in B. The position of Genomic DNA preparation and restriction analysis. Genomic DNA the 12 1ins2 mutation in exon 4 is shown. At where the was prepared from whole blood positions lymphocytes (patients 1.1, I.2, 11.2, published cDNA sequences differ (7-10), representing apparent po- II.3, 11.4, and controls), frozen lung tissue (patients II.5, II.6, CAP-2, lymorphisms, the nucleotide sequence of the deficient infants is and CAP-3), or formalin-fixed paraffin-embedded lung tissue (patient shown. Each transcript was represented at least two different II. 1) as described by previously (13, 14). 200 ng of genomic DNA was cDNA clones generated by RT-PCR from II.5 or *Pre- used in the PCR. After patients II.6. denaturation at 950C for 5 min, 35 cycles of mature termination codon. These sequence data are available from denaturation at 950C for 30 s, annealing at 590C for 30 s, and extension GenBank under accession numbers M2446 1, M 16764, J0276 1, and at 720C for 45 s were performed using a thermal cycler (National Lab- M19097. net Co., Woodbridge, NJ) followed by a 10-min incubation at 720C. The primers used were 5'-GGC CTT GTG TCC AGG GAC-3' in the sense orientation and 5'-TGT GTG TGA GAG TGA GGG TGT the 3' untranslated region and reported variants at positions AAG-3' in the antisense orientation ( 1 5), corresponding to positions 696, 697, 967, 1318, and 1972 1383-1400 and 2135-2158, (7-10).
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